Identification of the mechanism of action of a glucokinase activator from oral glucose tolerance test data in type 2 diabetic patients based on an integrated glucose-insulin model.

A mechanistic drug-disease model was developed on the basis of a previously published integrated glucose-insulin model by Jauslin et al. A glucokinase activator was used as a test compound to evaluate the model's ability to identify a drug's mechanism of action and estimate its effects on glucose and insulin profiles following oral glucose tolerance tests. A kinetic-pharmacodynamic approach was chosen to describe the drug's pharmacodynamic effects in a dose-response-time model. Four possible mechanisms of action of antidiabetic drugs were evaluated, and the corresponding affected model parameters were identified: insulin secretion, glucose production, insulin effect on glucose elimination, and insulin-independent glucose elimination. Inclusion of drug effects in the model at these sites of action was first tested one-by-one and then in combination. The results demonstrate the ability of this model to identify the dual mechanism of action of a glucokinase activator and describe and predict its effects: Estimating a stimulating drug effect on insulin secretion and an inhibiting effect on glucose output resulted in a significantly better model fit than any other combination of effect sites. The model may be used for dose finding in early clinical drug development and for gaining more insight into a drug candidate's mechanism of action.

Citation

Petra M Jauslin, Mats O Karlsson, Nicolas Frey. Identification of the mechanism of action of a glucokinase activator from oral glucose tolerance test data in type 2 diabetic patients based on an integrated glucose-insulin model. Journal of clinical pharmacology. 2012 Dec;52(12):1861-71

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PMID: 22174430

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